P
US8188090B2ActiveUtilityPatentIndex 38

Naphthylacetic acids

Assignee: FIROOZNIA FARIBORZPriority: Nov 17, 2008Filed: Nov 9, 2009Granted: May 29, 2012
Est. expiryNov 17, 2028(~2.4 yrs left)· nominal 20-yr term from priority
Inventors:FIROOZNIA FARIBORZLIN TAI-ANSO SUNG-SAUWANG BAOXIAYUN HONGYING
A61P 43/00A61P 37/08C07D 213/74C07D 295/192A61P 11/06C07D 401/12A61P 17/04A61P 17/00C07D 295/18C07D 487/10A61P 11/00C07D 239/42A61P 11/08A61P 11/02
38
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34
Claims

Abstract

The invention is concerned with the compounds of formula I: and pharmaceutically acceptable salts and esters thereof, wherein X, Q and R 1 -R 3 are defined in the detailed description and claims. The invention is also concerned with the compounds of formula Z: and pharmaceutically acceptable salts and esters thereof, wherein R 1 -R 3 are defined in the detailed description and claims. In addition, the present invention relates to methods of manufacturing and using the compounds of formula I and Z as well as pharmaceutical compositions containing such compounds. The compounds of formula I and Z are antagonists or partial agonists at the CRTH2 receptor and may be useful in treating diseases and disorders associated with that receptor such as asthma.

Claims

exact text as granted — not AI-modified
1. A compound of formula I: 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt or ester thereof, wherein: 
         X is O and Q is C(H); or alternatively, X is C(O) and Q is N; 
         R 1  is selected from the group consisting of:
 (a) hydrogen, 
 (b) halogen, 
 (c) lower alkyl optionally substituted by fluoro, 
 (d) lower alkoxy optionally substituted by fluoro, 
 (e) lower alkylsulfonyl, and 
 (f) cyano; 
 
         R 2  is hydrogen or lower alkyl; and 
         R 3  is selected from the group consisting of:
 (a) phenyl, pyridinyl, or pyrimidinyl, wherein said phenyl, pyridinyl, or pyrimidinyl is optionally substituted by one or more substituents independently selected from the group consisting of: (1) halogen, (2) lower alkyl optionally substituted by fluoro; (3) lower alkoxy optionally substituted by fluoro, and (4) cyano; 
 (b) lower alkoxycarbonyl; and 
 (c) S(O) 2 —R 4 , C(O)—R 4 , or C(O)—N(H)—R 4  wherein R 4  is selected from the group consisting of:
 (1) lower alkyl optionally substituted by fluoro, 
 (2) lower cycloalkyl, 
 (3) phenyl optionally substituted by: (i) halogen or (ii) lower alkyl optionally substituted by fluoro, 
 (4) benzyl or phenylethyl, and 
 (5) pyridinyl. 
 
 
       
     
     
       2. A compound of  claim 1  wherein X is O and Q is C(H). 
     
     
       3. A compound of  claim 1  wherein X is C(O) and Q is N. 
     
     
       4. A compound of  claim 1  wherein R 1  is hydrogen, halogen, or methyl. 
     
     
       5. A compound of  claim 1  wherein R 1  is fluoro. 
     
     
       6. A compound of  claim 1  wherein R 2  is hydrogen. 
     
     
       7. A compound of  claim 1  wherein R 2  is methyl. 
     
     
       8. A compound of  claim 1  wherein R 3  is phenyl, pyridinyl, or pyrimidinyl. 
     
     
       9. A compound of  claim 1  wherein R 3  is phenyl. 
     
     
       10. A compound of  claim 1  wherein R 3  is phenyl substituted with one or two substituents independently selected from the group consisting of chloro, fluoro, methyl, trifluoromethyl, and methoxy. 
     
     
       11. A compound of  claim 1  wherein R 3  is phenyl substituted at the 4 position on the phenyl ring with chloro, fluoro, methyl, trifluoromethyl, or methoxy. 
     
     
       12. A compound of  claim 1  wherein R 3  is —S(O) 2 —R 4  and R 4  is methyl, ethyl, propyl, isopropyl, cyclopropyl, cyclopentyl, or trifluoromethyl. 
     
     
       13. A compound of  claim 1  wherein R 3  is —S(O) 2 —R 4  and R 4  is phenyl optionally substituted by halogen or lower alkyl optionally substituted with fluoro. 
     
     
       14. A compound of  claim 1  wherein R 3  is —S(O) 2 —R 4  and R 4  is phenyl optionally substituted once or twice by fluoro. 
     
     
       15. A compound of  claim 1  wherein R 3  is —C(O)—R 4  and R 4  is methyl, ethyl, propyl, isopropyl, cyclopropyl, cyclopentyl, or trifluoromethyl. 
     
     
       16. A compound of  claim 1  wherein R 3  is —C(O)—R 4  and R 4  is phenyl optionally substituted by halogen or lower alkyl. 
     
     
       17. A compound of  claim 1  wherein R 3  is —C(O)—R 4  and R 4  is phenyl optionally substituted once or twice by fluoro. 
     
     
       18. A compound of  claim 1  wherein R 3  is —C(O)—N(H)—R 4  and R 4  is methyl, ethyl, propyl, isopropyl, cyclopropyl, cyclopentyl, or trifluoromethyl. 
     
     
       19. A compound of  claim 1  wherein R 3 —C(O)—N(H)—R 4  and R 4  is methyl, ethyl, propyl, isopropyl, cyclopropyl, cyclopentyl, or trifluoromethyl. 
     
     
       20. A compound of  claim 1  wherein R 3  is —C(O)—N(H)—R 4  and R 4  is phenyl optionally substituted by halogen or lower alkyl. 
     
     
       21. A compound of  claim 1  wherein R 3  is —C(O)—N(H)—R 4  and R 4  is phenyl optionally substituted once or twice by fluoro. 
     
     
       22. A compound of  claim 1  wherein R 3  is pyridinyl. 
     
     
       23. A compound of  claim 1  selected from the group consisting of:
 [4-(4-Ethanesulfonyl-piperazine-1-carbonyl)-6-fluoro-3-methyl-naphthalen-2-yl]-acetic acid; 
 [4-(4-Ethanesulfonyl-piperazine-1-carbonyl)-6-fluoro-naphthalen-2-yl]-acetic acid; 
 [6-Fluoro-4-(4-methanesulfonyl-piperazine-1-carbonyl)-3-methyl-naphthalen-2-yl]-acetic acid; 
 {6-Fluoro-3-methyl-4-[4-(propane-2-sulfonyl)-piperazine-1-carbonyl]-naphthalen-2-yl}-acetic acid; 
 [6-Fluoro-3-methyl-4-(4-trifluoromethanesulfonyl-piperazine-1-carbonyl)-naphthalen-2-yl]-acetic acid; 
 [4-(4-Cyclopropanesulfonyl-piperazine-1-carbonyl)-6-fluoro-3-methyl-naphthalen-2-yl]-acetic acid; 
 {6-Fluoro-4-[4-(propane-1-sulfonyl)-piperazine-1-carbonyl]-naphthalen-2-yl}-acetic acid; 
 [4-(4-Cyclopentanesulfonyl-piperazine-1-carbonyl)-6-fluoro-3-methyl-naphthalen-2-yl]-acetic acid; 
 [4-(4-Benzenesulfonyl-piperazine-1-carbonyl)-6-fluoro-3-methyl-naphthalen-2-yl]-acetic acid; 
 {6-Fluoro-4-[4-(4-fluoro-benzenesulfonyl)-piperazine-1-carbonyl]-3-methyl-naphthalen-2-yl}-acetic acid; 
 [6-Fluoro-3-methyl-4-(4-phenylmethanesulfonyl-piperazine-1-carbonyl)-naphthalen-2-yl]-acetic acid; 
 {6-Fluoro-4-[4-(2-fluoro-benzenesulfonyl)-piperazine-1-carbonyl]-3-methyl-naphthalen-2-yl}-acetic acid; 
 {4-[4-(3,4-Difluoro-benzenesulfonyl)-piperazine-1-carbonyl]-6-fluoro-3-methyl-naphthalen-2-yl}-acetic acid; 
 {6-Fluoro-4-[4-(3-fluoro-benzenesulfonyl)-piperazine-1-carbonyl]-3-methyl-naphthalen-2-yl}-acetic acid; 
 {4-[4-(2,4-Difluoro-benzenesulfonyl)-piperazine-1-carbonyl]-6-fluoro-3-methyl-naphthalen-2-yl}-acetic acid; 
 [4-(4-Benzenesulfonyl-piperazine-1-carbonyl)-6-trifluoromethyl-naphthalen-2-yl]-acetic acid; 
 [4-(4-Benzenesulfonyl-piperazine-1-carbonyl)-6-trifluoromethoxy-naphthalen-2-yl]-acetic acid; 
 {6-Fluoro-4-[4-(4-fluoro-phenyl)-piperazine-1-carbonyl]-3-methyl-naphthalen-2-yl}-acetic acid; 
 [6-Fluoro-3-methyl-4-(4-pyridin-2-yl-piperazine-1-carbonyl)-naphthalen-2-yl]-acetic acid; 
 {6-Fluoro-4-[4-(2-fluoro-phenyl)-piperazine-1-carbonyl]-3-methyl-naphthalen-2-yl}-acetic acid; 
 [6-Fluoro-3-methyl-4-(4-phenyl-piperazine-1-carbonyl)-naphthalen-2-yl]-acetic acid; 
 [6-Fluoro-3-methyl-4-(4-pyrimidin-2-yl-piperazine-1-carbonyl)-naphthalen-2-yl]-acetic acid; 
 [6-Fluoro-3-methyl-4-(4-m-tolyl-piperazine-1-carbonyl)-naphthalen-2-yl]-acetic acid; 
 {6-Fluoro-3-methyl-4-[4-(3-trifluoromethyl-phenyl)-piperazine-1-carbonyl]-naphthalen-2-yl}-acetic acid; 
 {6-Fluoro-4-[4-(2-methoxy-phenyl)-piperazine-1-carbonyl]-3-methyl-naphthalen-2-yl}-acetic acid; 
 {6-Fluoro-4-[4-(3-methoxy-phenyl)-piperazine-1-carbonyl]-3-methyl-naphthalen-2-yl}-acetic acid; 
 {4-[4-(2-Ethyl-phenyl)-piperazine-1-carbonyl]-6-fluoro-3-methyl-naphthalen-2-yl}-acetic acid; 
 {4-[4-(3,5-Bis-trifluoromethyl-phenyl)-piperazine-1-carbonyl]-6-fluoro-3-methyl-naphthalen-2-yl}-acetic acid; 
 {6-Fluoro-4-[4-(4-methoxy-phenyl)-piperazine-1-carbonyl]-3-methyl-naphthalen-2-yl}-acetic acid; 
 {4-[4-(2,4-Difluoro-phenyl)-piperazine-1-carbonyl]-6-fluoro-3-methyl-naphthalen-2-yl}-acetic acid; 
 {4-[4-(3,5-Dimethoxy-phenyl)-piperazine-1-carbonyl]-6-fluoro-3-methyl-naphthalen-2-yl}-acetic acid; 
 {6-Fluoro-3-methyl-4-[4-(2-trifluoromethyl-phenyl)-piperazine-1-carbonyl]-naphthalen-2-yl}-acetic acid; 
 [6-Fluoro-3-methyl-4-(4-p-tolyl-piperazine-1-carbonyl)-naphthalen-2-yl]-acetic acid; 
 {4-[4-(3,5-Dichloro-phenyl)-piperazine-1-carbonyl]-6-fluoro-3-methyl-naphthalen-2-yl}-acetic acid; 
 {4-[4-(4-Chloro-phenyl)-piperazine-1-carbonyl]-6-fluoro-3-methyl-naphthalen-2-yl}-acetic acid; 
 {6-Fluoro-3-methyl-4-[4-(4-trifluoromethyl-phenyl)-piperazine-1-carbonyl]-naphthalen-2-yl}-acetic acid; 
 {4-[4-(2-Chloro-phenyl)-piperazine-1-carbonyl]-6-fluoro-3-methyl-naphthalen-2-yl}-acetic acid; 
 {4-[4-(3-Chloro-phenyl)-piperazine-1-carbonyl]-6-fluoro-3-methyl-naphthalen-2-yl}-acetic acid; 
 {6-Fluoro-3-methyl-4-[4-(5-trifluoromethyl-pyridin-2-yl)-piperazine-1-carbonyl]-naphthalen-2-yl}-acetic acid; 
 {4-[4-(3,5-Dichloro-pyridin-4-yl)-piperazine-1-carbonyl]-6-fluoro-3-methyl-naphthalen-2-yl}-acetic acid; 
 {4-[4-(4-Cyano-phenyl)-piperazine-1-carbonyl]-6-fluoro-3-methyl-naphthalen-2-yl}-acetic acid; 
 4-(3-Carboxymethyl-7-fluoro-naphthalen-1-yloxy)-piperidine-1-carboxylic acid tert-butyl ester; 
 [6-Fluoro-4-(1-methanesulfonyl-piperidin-4-yloxy)-naphthalen-2-yl]-acetic acid; 
 [4-(1-Ethanesulfonyl-piperidin-4-yloxy)-6-fluoro-naphthalen-2-yl]-acetic acid; 
 {6-Fluoro-4-[1-(propane-2-sulfonyl)-piperidin-4-yloxy]-naphthalen-2-yl}-acetic acid; 
 [4-(1-Cyclopropanesulfonyl-piperidin-4-yloxy)-6-fluoro-naphthalen-2-yl]-acetic acid; 
 [4-(1-Cyclopentanesulfonyl-piperidin-4-yloxy)-6-fluoro-naphthalen-2-yl]-acetic acid; 
 [4-(1-Benzenesulfonyl-piperidin-4-yloxy)-6-fluoro-naphthalen-2-yl]-acetic acid; 
 {6-Fluoro-4-[1-(3-fluoro-benzenesulfonyl)-piperidin-4-yloxy]-naphthalen-2-yl}-acetic acid; 
 {6-Fluoro-4-[1-(4-fluoro-benzenesulfonyl)-piperidin-4-yloxy]-naphthalen-2-yl}-acetic acid; 
 {6-Fluoro-4-[1-(pyridine-3-sulfonyl)-piperidin-4-yloxy]-naphthalen-2-yl}-acetic acid; 
 [6-Fluoro-4-(1-phenylmethanesulfonyl-piperidin-4-yloxy)-naphthalen-2-yl]-acetic acid; 
 [4-(1-Acetyl-piperidin-4-yloxy)-6-fluoro-naphthalen-2-yl]-acetic acid; 
 [6-Fluoro-4-(1-propionyl-piperidin-4-yloxy)-naphthalen-2-yl]-acetic acid; 
 [6-Fluoro-4-(1-isobutyryl-piperidin-4-yloxy)-naphthalen-2-yl]-acetic acid; 
 [4-(1-Cyclopropanecarbonyl-piperidin-4-yloxy)-6-fluoro-naphthalen-2-yl]-acetic acid; 
 [4-(1-Cyclopentanecarbonyl-piperidin-4-yloxy)-6-fluoro-naphthalen-2-yl]-acetic acid; 
 [4-(1-Benzoyl-piperidin-4-yloxy)-6-fluoro-naphthalen-2-yl]-acetic acid; 
 {6-Fluoro-4-[1-(2-fluoro-benzoyl)-piperidin-4-yloxy]-naphthalen-2-yl}-acetic acid; 
 {6-Fluoro-4-[1-(3-fluoro-benzoyl)-piperidin-4-yloxy]-naphthalen-2-yl}-acetic acid; 
 {6-Fluoro-4-[1-(4-fluoro-benzoyl)-piperidin-4-yloxy]-naphthalen-2-yl}-acetic acid; 
 [6-Fluoro-4-(1-phenylacetyl-piperidin-4-yloxy)-naphthalen-2-yl]-acetic acid; 
 [4-(1-Ethylcarbamoyl-piperidin-4-yloxy)-6-fluoro-naphthalen-2-yl]-acetic acid; 
 {6-Fluoro-4-[1-(2-fluoro-phenylcarbamoyl)-piperidin-4-yloxy]-naphthalen-2-yl}-acetic acid; 
 {6-Fluoro-4-[1-(3-fluoro-phenylcarbamoyl)-piperidin-4-yloxy]-naphthalen-2-yl}-acetic acid; 
 {6-Fluoro-4-[1-(4-fluoro-phenylcarbamoyl)-piperidin-4-yloxy]-naphthalen-2-yl}-acetic acid; 
 [6-Fluoro-4-(1-phenethylcarbamoyl-piperidin-4-yloxy)-naphthalen-2-yl]-acetic acid and any pharmaceutically acceptable salt or ester thereof. 
 
     
     
       24. A pharmaceutically acceptable salt of a compound of  claim 20 . 
     
     
       25. A pharmaceutically acceptable ester of a compound of  claim 20 . 
     
     
       26. A compound of  claim 1  which is [4-(4-Benzenesulfonyl-piperazine-1-carbonyl)-6-fluoro-3-methyl-naphthalen-2-yl]-acetic acid. 
     
     
       27. A compound of  claim 1  which is {4-[4-(4-Chloro-phenyl)-piperazine-1-carbonyl]-6-fluoro-3-methyl-naphthalen-2-yl}-acetic acid. 
     
     
       28. A compound of  claim 1  which is [4-(1-Benzenesulfonyl-piperidin-4-yloxy)-6-fluoro-naphthalen-2-yl]-acetic acid. 
     
     
       29. A compound of  claim 1  which is [6-Fluoro-4-(1-phenylmethanesulfonyl-piperidin-4-yloxy)-naphthalen-2-yl]-acetic acid. 
     
     
       30. A compound of  claim 1  which is [6-Fluoro-4-(1-phenylacetyl-piperidin-4-yloxy)-naphthalen-2-yl]-acetic acid. 
     
     
       31. A compound of  claim 1  which is {6-Fluoro-4-[1-(4-fluoro-phenylcarbamoyl)-piperidin-4-yloxy]-naphthalen-2-yl}-acetic acid. 
     
     
       32. A pharmaceutical composition comprising a therapeutically effective amount of a compound according to  claim 1  and a pharmaceutically acceptable carrier. 
     
     
       33. A compound of formula Z: 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt or ester thereof, wherein: 
         R 1  is selected from the group consisting of:
 (a) hydrogen, 
 (b) halogen, 
 (c) lower alkyl optionally substituted by fluoro, 
 (d) lower alkoxy optionally substituted by fluoro, 
 (e) lower alkylsulfonyl, and 
 (f) cyano; 
 
         R 2  is hydrogen or lower alkyl; and 
         R 3  is S(O) 2 —R 4  wherein R 4  is selected from the group consisting of:
 (a) phenyl or benzyl, wherein said phenyl or benzyl is optionally substituted by one or more substituents of: (1) halogen or (2) lower alkyl optionally substituted by fluoro; and 
 (b) lower alkyl optionally substituted by fluoro. 
 
       
     
     
       34. A compound of  claim 33  selected from the group consisting of:
 [4-(6-Benzenesulfonyl-2,6-diaza-spiro[3.3]heptane-2-carbonyl)-6-fluoro-3-methyl-naphthalen-2-yl]-acetic acid; 
 [6-Fluoro-3-methyl-4-(6-phenylmethanesulfonyl-2,6-diaza-spiro[3.3]heptane-2-carbonyl)-naphthalen-2-yl]-acetic acid; and 
 any pharmaceutically acceptable salt or ester thereof.

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